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Abstract Background Hyperlipidemia damages vascular wall and serves as a foundation for diseases such as atherosclerosis, hypertension and stiffness. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is implicated in vascular dysfunction associated with hyperlipidemia-induced vascular injury. Sodium tanshinone IIA sulfonate (STS), a well-established cardiovascular protective drug with recognized anti-inflammatory, antioxidant, and vasodilatory properties, is yet to be thoroughly investigated for its impact on vascular relaxant imbalance induced by hyperlipidemia. Methods In this study, we treated ApoE-knockout (ApoE-/-) mouse with STS and assessed the activation of the NLRP3 inflammasome, expression of MMP2/9, integrity of elastic fibers, and vascular constriction and relaxation. Results Our findings reveal that STS intervention effectively preserves elastic fibers, significantly restores aortic relaxation function in ApoE-/- mice, and reduces their excessive constriction. Furthermore, STS inhibits the phosphorylation of spleen tyrosine kinase (SYK), suppresses NLRP3 inflammasome activation, and reduces MMP2/9 expression. Conclusions These results demonstrate that STS protects vascular relaxation against hyperlipidemia-induced damage through modulation of the SYK-NLRP3 inflammasome-MMP2/9 pathway. This research provides novel insights into the mechanisms underlying vascular relaxation impairment in a hyperlipidemic environment and uncovers a unique mechanism by which STS preserves vascular relaxation, offering valuable foundational research evidence for its clinical application in promoting vascular health.

Abstract Background Endothelial progenitor cells (EPCs) transplantation is one of the effective therapies for neointima associated with endothelial injury. Diabetes impairs the function of EPCs and cumbers neointima prevention of EPC transplantation with an ambiguous mechanism. Sodium Tanshinone IIA Sulfonate (STS) is an endothelium-protective drug but whether STS protects EPCs in diabetes is still unknown. Methods EPCs were treated with High Glucose (HG), STS, and Nucleotide-binding Domain-(NOD) like Receptor 3 (NLRP3), caspase-1, the Receptor of Advanced Glycation End products (AGEs) (RAGE) inhibitors, Thioredoxin-Interacting Protein (TXNIP) siRNA, and EPC proliferation, differentiation functions, and senescence were detected. The treated EPCs were transplanted into db/db mice with the wire-injured Common Carotid Artery (CCA), and the CD31 expression and neointima were detected in the CCA inner wall. Results We found that STS inhibited HG-induced expression of NLRP3, the production of active caspase-1 (p20) and mature IL-1β, the expression of catalase (CAT) cleavage, γ-H2AX, and p21 in EPCs. STS restored the expression of Ki67, CD31 and von Willebrand Factor (vWF) in EPCs; AGEs were found in the HG-treated EPCs supernatant, and RAGE blocking inhibited the expression of TXNIP and the production of p20, which was mimicked by STS. STS recovered the expression of CD31 in the wire-injured CCA inner wall and the prevention of neointima in diabetic mice with EPCs transplantation. Conclusion STS inhibits the aggravated neointima hyperplasia by protecting the proliferation and differentiation functions of EPC and inhibiting EPC senescence in diabetic mice. The mechanism is related to the preservation of CAT activity by inhibiting the RAGE-TXNIP-NLRP3 inflammasome pathway.

Background: Patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) therapy may experience further damage to the vascular endothelium, leading to increased inflammatory response and in-stent thrombosis. In many clinical studies, sodium tanshinone IIA sulfonate injection (STS) has been found to reduce inflammatory factors and enhance vascular endothelial function in patients with ACS while improving the prognosis of PCI. However, to date, there has been no systematic review assessing the effectiveness and safety of STS on inflammatory factors and vascular endothelial function.Purpose: The aim of this study is to systematically review the effects of STS on inflammatory factors and endothelial function in patients with ACS treated with PCI.Methods: Until October 2022, eight literature databases and two clinical trial registries were searched for randomized controlled trials (RCTs) investigating STS treatment for ACS patients undergoing PCI. The quality of the included studies was assessed using the Cochrane Risk Assessment Tool 2.0. Meta-analysis was performed using RevMan 5.4 software.Results: Seventeen trials met the eligibility criteria, including 1,802 ACS patients undergoing PCI. The meta-analysis showed that STS significantly reduced high-sensitivity C-reactive protein (hs-CRP) levels (mean difference [MD = −2.35, 95% CI (−3.84, −0.86), p = 0.002], tumor necrosis factor-alpha (TNF-α) levels (standard mean difference [SMD = −3.29, 95%CI (−5.15, −1.42), p = 0,006], matrix metalloproteinase-9 (MMP-9) levels [MD = −16.24, 95%CI (−17.24, −15.24), p < 0.00001], and lipid peroxidation (LPO) levels [MD = −2.32, 95%CI (−2.70, −1.93), p < 0.00001], and increased superoxide dismutase (SOD) levels [SMD = 1.46, 95%CI (0.43, 2.49), p = 0,006] in patients with ACS. In addition, STS significantly decreased the incidence of major adverse cardiovascular events (relative risk = 0.54, 95%CI [0.44, 0.66], p < 0.00001). The quality of evidence for the outcomes was assessed to be very low to medium.Conclusion: STS can safely and effectively reduce the levels of hs-CRP, TNF-α, MMP-9, and LPO and increase the level of SOD in patients with ACS treated with PCI. It can also reduce the incidence of adverse cardiovascular events. However, these findings require careful consideration due to the small number of included studies, high risk of bias, and low to moderate evidence. In the future, more large-scale and high-quality RCTs will be needed as evidence in clinical practice.

Objective To investigate the effects of eukaryotic elongation factor-2 kinase (eEF2K) gene transfection and sodium tanshinone Ⅱ A sulfonate (STS) on proliferation, invasion and migration of lung adenocarcinoma cell line A549 and its mechanism. Methods The optimal concentration of STS was screened out by preliminary experiment. A549 cells were divided into siRNA-NC group (transfected with siRNA-NC), siRNA-eEF2K group (transfected with siRNA-eEF2K), siRNA-NC+STS group (treated with 10 μg/mL STS after siRNA-NC) and siRNA-eEF2K+STS group (treated with 10 μg/mL STS after siRNA-eEF2K).The survival rate, clone formation, cell counting of transmembrane cells, migration and apoptosis of A549 cells were detected by CCK-8 method, clone formation test, Transwell chamber test, scratch test and flow cytometry. The protein expression levels of protein kinase B (AKT), phosphorylation (p)-AKT, Ki67, matrix metalloproteinase-2 (MMP-2) and B-cell lymphoma-2 genes (Bcl-2) were detected by Western blot. Results Compared with those in siRNA-NC group, the cell survival rate, clone formation rate, number of transmembrane cells, migration rate and p-AKT, Ki67, MMP-2 and Bcl-2 in proteins siRNA-eEF2K+STS group were significantly lower, while the apoptosis rate was significantly higher (P＜0.05). The siRNA-eEF2K+STS group had the largest range of changes in the above indexes. Conclusions Silencing eEF2K combined with STS can synergistically inhibit the proliferation, invasion and migration of A549 cells and promote cell apoptosis. The mechanism is potentially related to the inhibition of protein expression of p-AKT, Ki67, MMP-2 and Bcl-2.

Although the antitumor efficacy of immune checkpoint blockade (ICB) has been proved in colorectal cancer (CRC), the results are unsatisfactory, presumably owing to the presence of tryptophan metabolism enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2). However, only a few dual inhibitors for IDO1 and TDO2 have been reported. Here, we discovered that sodium tanshinone IIA sulfonate (STS), a sulfonate derived from tanshinone IIA (TSN), reduced the enzymatic activities of IDO1 and TDO2 with a half inhibitory concentration (IC50) of less than 10 μM using enzymatic assays for natural product screening. In IDO1- or TDO2- overexpressing cell lines, STS decreased kynurenine (kyn) synthesis. STS also reduced the percentage of forkhead box P3 (FOXP3) T cells in lymphocytes from the mouse spleen cocultured with CT26. In vivo, STS suppressed tumor growth and enhanced the antitumor effect of the programmed cell death 1 (PD1) antibody. Compared with anti-PD1 (α-PD1) monotherapy, combined with STS had lower level of plasma kynurenine. Immunofluorescence assay suggested that STS decreased the number of FOXP3+ T cells and increased the number of CD8+ T cells in tumors. Flow cytometry analysis of immune cells in tumor tissues demonstrated an increase in the percentage of tumor-infiltrating CD8+ T cells. According to our findings, STS acts as an immunotherapy agent in CRC by inhibiting both IDO1 and TDO2.

Background: Lipid-lowering therapy is very important in secondary prevention of coronary heart disease (CHD). In many clinical trials, it has been found that Sodium Tanshinone IIA Sulfonate Injection (STS) have a lipid-lowering effect while reducing major cardiovascular events in patients with CHD. However, up to now, there is no system review on the effectiveness and safety of STS affecting blood lipids.Purpose: The aim of this review is to systematically assess the effects of STS on blood lipid levels in patients with CHD.Methods: Until Mar 2021, five databases (PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, and Wanfang Database) were searched for randomized controlled trials (RCTs) about STS treating patients with CHD. Risk bias was assessed for included studies according to Cochrane handbook. The primary outcome was total cholesterol (TC). The secondary outcomes were triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), and adverse events (AEs).Results: A total of 27 trials including 2,445 CHD patients met the eligibility criteria. Most trials had high risks in random sequence generation, allocation concealment, blinding of patients and personal, blinding of outcome assessment. Meta-analysis showed that STS significantly reduced plasma TC levels [MD = −1.34 mmol/l 95% CI (−1.59, −1.09), p < 0.00001, I2 = 98%], TG levels [MD = −0.49 mmol/l 95% CI (−0.62, −0.35), p < 0.00001, I2 = 97%], LDL-c levels [MD = −0.68 mmol/l (−0.80, −0.57), p < 0.00001, I2 = 96%], increased HDL-c levels [MD = 0.26 mmol/l (0.15, 0.37), p < 0.00001, I2 = 97%], without increasing the incidence of AEs [RR = 1.27 95% CI (0.72, 2.27), p = 0.94, I2 = 0%] in patients with CHD.Conclusion: STS can safely and effectively reduce plasma TC, TG and LDL-c levels in patients with CHD, and improve plasma HDL-c levels. However, these findings require careful recommendation due to the low overall quality of RCTs at present. More multi-center, randomized, double-blind, placebo-controlled trials which are designed follow the CONSORT 2010 guideline are needed.

Non-alcoholic fatty liver disease (NAFLD) is becoming an epidemic disease in adults and children worldwide. Importantly, there are currently no approved treatments available for NAFLD. This study aims to investigate the potential applications of sodium tanshinone IIA sulfonate (STS) on improving the NAFLD condition using both in vitro and in vivo approaches. The results showed that STS markedly inhibited lipid accumulation in oleic acid (OA) and palmitic acid (PA) treated HepG2 and primary immortalized human hepatic (PIH) cells. STS suppressed lipogenesis by inhibiting expression of sterol regulatory element binding transcription factor 1 (SREBF1), fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD). In addition, STS reduced inflammation in cells treated with OA-PA, shown by decreased transcriptional levels of tumor necrosis factor (TNF), transforming growth factor beta 1 (TGFB1) and interleukin 1 beta (IL1B). Consistently, protective effects on hepatic steatosis in db/db mice were observed after STS administration, demonstrated by decreased lipid accumulation in mouse hepatocytes. This protective effect might be associated with STS induced activation of sirtuin 1 (SIRT1)/protein kinase AMP-activated catalytic subunit alpha 1 (PRKAA1) pathways. Our findings suggest a potential therapeutic role for STS in the treatment of NAFLD.

Hemorrhage stroke is a severe vascular disease of the brain with a high mortality rate in humans. Salvia miltiorrhiza Bunge (Danshen) is a well-known Chinese Materia Medica for treating cerebral vascular and cardiovascular diseases in traditional Chinese medicine. Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of tanshinone IIA, which is the main active ingredient of Danshen. In our previous study, we established a zebrafish model of cerebral hemorrhage and found that STS dramatically decreased both the hemorrhage rate and hemorrhage area, although the underlying mechanism was not fully elucidated. We conducted a transcriptome analysis of the protective effect of STS against atorvastatin (Ator)-induced cerebral hemorrhage in zebrafish using RNA-seq technology. RNA-seq revealed 207 DEGs between the Ator-treated group and control group; the expression levels of 53 DEGs between the Ator-treated group and control group were reversed between the STS + Ator-treated group and Ator-treated group. GO enrichment analysis indicated that these 53 DEGs encode proteins with roles in hemoglobin complexes, oxygen carrier activity and oxygen binding, etc. KEGG analysis suggested that these 53 DEGs were most enriched in three items, namely, porphyrin and chlorophyll metabolism, ferroptosis, and the HIF-1 signaling pathway. The PPI network analysis identified 12 hub genes, and we further verified that Ator elevated the mRNA expression levels of hemoglobin (hbae1.3, hbae3, hbae5, hbbe2, and hbbe3), carbonic anhydrase (cahz), HIF-1 (hif1al2) and Na+/H+ exchanger (slc4a1a and slc9a1) genes, while STS significantly suppressed these genes. In addition, we found that pharmacological inhibition of PI3K/Akt, MAPKs, and mTOR signaling pathways by specific inhibitors partially attenuated the protective effect of STS against Ator-induced cerebral hemorrhage in zebrafish, regardless of mTOR inhibition. We concluded that hemoglobin, carbonic anhydrase, Na+/H+ exchanger and HIF-1 genes might be potential biomarkers of Ator-induced cerebral hemorrhage in zebrafish, as well as pharmacological targets of STS. Moreover, HIF-1 and its regulators, i.e., the PI3K/Akt and MAPK signaling pathways, were involved in the protective effect of STS against Ator-induced cerebral hemorrhage. This study also provided evidence of biomarkers involved in hemorrhage stroke and improved understanding of the effects of HMG-COA reductase inhibition on vascular permeability and cerebral hemorrhage.

Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivate of tanshinone IIA (Tan IIA) which is an active lipophilic constitute of Chinese Materia Medica Salvia miltiorrhiza Bge. (Danshen). STS presents multiple pharmacological activities, including anti-oxidant, anti-inflammation and anti-apoptosis, and has been approved for treatment of cardiovascular diseases by China State Food and Drug Administration (CFDA). In this review, we comprehensively summarized the pharmacological activities and pharmacokinetics of STS, which could support the further application and development of STS. In the recent decades, numerous experimental and clinical studies have been conducted to investigate the potential treatment effects of STS in various diseases, such as heart diseases, brain diseases, pulmonary diseases, cancers, sepsis and so on. The underlying mechanisms were most related to anti-oxidative and anti-inflammatory effects of STS via regulating various transcription factors, such as NF-κB, Nrf2, Stat1/3, Smad2/3, Hif-1α and β-catenin. Iron channels, including Ca2+, K+ and Cl− channels, were also the important targets of STS. Additionally, we emphasized the differences between STS and Tan IIA despite the interchangeable use of Tan IIA and STS in many previous studies. It is promising to improve the efficacy and reduce side effects of chemotherapeutic drug by the combination use of STS in canner treatment. The application of STS in pregnancy needs to be seriously considered. Moreover, the drug-drug interactions between STS and other drugs needs to be further studied as well as the complications of STS.

The level of maladaptive myocardial remodeling consistently contributes to the poor prognosis of patients following a myocardial infarction (MI). In this study, we investigated whether and how sodium tanshinone IIA sulfonate (STS) would attenuate the post-infarct cardiac remodeling in mice model of MI developing after surgical ligation of the left coronary artery. All mice subjected to experimental MI or to the sham procedure were then treated for the following 4 weeks, either with STS or with a vehicle alone. Results of our studies indicated that STS treatment of MI mice prevented the left ventricular dilatation and improved their cardiac function. Results of further tests, aimed at mechanistic explanation of the beneficial effects of STS, indicated that treatment with this compound enhanced the autophagy and, at the same time, inhibited apoptosis of the cardiomyocytes. Meaningfully, we have also established that myocardium of STS-treated mice displayed significantly higher levels of adenosine monophosphate kinase than their untreated counterparts and that this effect additionally associated with the significantly diminished activities of apoptotic promoters: mammalian target of rapamycin and P70S6 kinase. Moreover, we also found that additional administration of the adenosine monophosphate kinase inhibitor (compound C) or autophagy inhibitor (chloroquine) practically eliminated the observed beneficial effects of STS. In conclusion, we suggest that the described multistage mechanism triggered by STS treatment enhanced autophagy, thereby attenuating pathologic remodeling of the post-infarct hearts.

Aberrant activation of hypoxia-inducible factor (HIF)-1α is frequently encountered and promotes oxidative stress and inflammation in chronic obstructive pulmonary disease (COPD). The present study investigated whether sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of tanshinone IIA, can mediate its effect through inhibiting HIF-1α–induced oxidative stress and inflammation in cigarette smoke (CS)-induced COPD in mice. Here, we found that STS improved pulmonary function, ameliorated emphysema and decreased the infiltration of inflammatory cells in the lungs of CS-exposed mice. STS reduced CS- and cigarette smoke extract (CSE)-induced upregulation of tumor necrosis factor (TNF)-α and interleukin (IL)-1β in the lungs and macrophages. STS also inhibited CSE-induced reactive oxygen species (ROS) production, as well as the upregulation of heme oxygenase (HO)-1, NOX1 and matrix metalloproteinase (MMP)-9 in macrophages. In addition, STS suppressed HIF-1α expression in vivo and in vitro, and pretreatment with HIF-1α siRNA reduced CSE-induced elevation of TNF-α, IL-1β, and HO-1 content in the macrophages. Moreover, we found that STS inhibited CSE-induced the phosphorylation of ERK, p38 MAPK and JNK in macrophages, and inhibition of these signaling molecules significantly repressed CSE-induced HIF-1α expression. It indicated that STS inhibits CSE-induced HIF-1α expression likely by blocking MAPK signaling. Furthermore, STS also promoted HIF-1α protein degradation in CSE-stimulated macrophages. Taken together, these results suggest that STS prevents COPD development possibly through the inhibition of HIF-1α signaling, and may be a novel strategy for the treatment of COPD.